Opioids are therapeutically active agents that have a morphine-like action in the body. Their main use is as analgesics for treating moderate to severe pain, including acute pain such as post-operative pain and severe, chronic, disabling pain of terminal conditions such as cancer. They are also frequently used as anesthetics for pre-operative sedation. Some opioids are also used to treat diarrhea. In recent years there has been an increased use of opioids in the management of non-malignant chronic pain following the recognition that dependence is rare when the drug is being used for pain relief.
In addition to analgesia and anaesthesia, opioids are used to treat or prevent cough (in particular codeine, dextromethorphan and hydrocodone), to treat diarrhea, anxiety (in particular oxymorphone) and for detoxification and addiction (in particular methadone, buprenorphine, naloxone and naltrexone).
Opioids include: endogenous opioid-peptides such as endorphins, dynorphins and enkephalins; opium alkaloids such as codeine, morphine and thebaine; semisynthetic derivatives such as diacetylmorphine (heroin), dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone and oxymorphone; anilidopiperidines such as fentanyl, alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl and ohmefentanyl; phenylpiperidines such as nocaine, pethidine (meperidine), ketobemidone, MPPP, allylprodine, prodine and PEPAP; diphenylpropylamine derivatives such as propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone, levo-alphacetylmethadol (LAAM), loperamide and diphenoxylate; benzomorphane derivatives such as pentazocine and phenazocine; oripavine derivatives such as buprenorphine and etorphine; morphinan derivatives such as butorphanol, nalbuphine, levorphanol and levomethorphan; and other opioids such as dezocine, lefetamine, tilidine and tramadol.
Many opioids exhibit low water solubility and are practically insoluble in water. This hinders their effective use, particularly for oral delivery in base form and so water soluble salt forms are preferred, such as sulphates (e.g. morphine sulphate), citrates (e.g. fentanyl and sufentanil salts), tartrates (e.g. hydrocodone bitartrate), phosphates (e.g. codeine salt), hydrobromides (e.g. dextrometorphan salt), hydrochlorides (e.g. oxycodone, oxymorphone, hydromorphone, buprenorphine and tramadol salts).
WO 2004/011537 describes the formation of solid, porous beads comprising a three dimensional open-cell lattice of a water-soluble polymeric material. These are typically “templated” materials formed by the removal of both water and a non-aqueous dispersed phase from a high internal phase emulsion (HIPE) which has a polymer dissolved in the aqueous phase. The beads are formed by dropping the HIPE emulsion into a low temperature fluid such as liquid nitrogen, then freeze-drying the particles formed to remove the bulk of the aqueous phase and the dispersed phase. This leaves behind the polymer in the form of a “skeletal” structure. The beads dissolve rapidly in water and have the remarkable property that a water-insoluble component dispersed in the dispersed phase of the emulsion prior to freezing and drying can also be dispersed in water on solution of the polymer skeleton of the beads.
WO 2005/011636 discloses a non-emulsion based spray drying process for forming “solid amorphous dispersions” of drugs in polymers. In this method a polymer and a low-solubility drug are dissolved in a solvent and spray-dried to form dispersions in which the drug is mostly present in an amorphous form rather than in a crystalline form.
Unpublished co-pending applications (GB 0501835 of 28 Jan. 2005 and GB 0613925 filed on 13 Jul. 2006) describe how materials which will form a nano-dispersion in water can be prepared, preferably by a spray-drying process. In the first of these applications the water insoluble materials is dissolved in the solvent-phase of an emulsion. In the second, the water-insoluble materials are dissolved in a mixed solvent system and co-exist in the same phase as a water-soluble structuring agent. In both cases the liquid is dried above ambient temperature (above 20° C.), such as by spray drying, to produce particles of the structuring agent, as a carrier, with the water-insoluble materials dispersed therein. When these particles are placed in water they dissolve, forming a nano-dispersion of the water-insoluble material with particles typically below 300 nm. This scale is similar to that of virus particles, and the water-insoluble material behaves as though it were in solution.
In the present application the term “ambient temperature” means 20° C. and all percentages are percentages by weight unless otherwise specified.